The present invention relates to the use of substituted bicyclo[3.3.1]nonane-2,4,9-triones, in particular clusianone and clusianone derivatives, as active pharmaceutical ingredients or active ingredients of medicaments, in particular for producing medicaments for the prophylactic and/or therapeutic (curative) treatment of neoplastic or cancerous diseases and of viral diseases. The present invention equally relates to substituted bicyclo[3.3.1]nonane-2,4,9-triones as pharmaceutically active ingredients of medicaments or pharmaceutical compositions, in particular cytostatics and antiviral compositions (virustatics). The present invention further relates to the use of substituted bicyclo[3.3.1]nonane-2,4,9-triones as topoisomerase inhibitors and/or telomerase inhibitors and as regulators within MAP kinase signal transduction.
Neoplastic or cancerous diseases are not a single pathological state but are generic terms for a large number of different types of malignant diseases. Virtually every tissue in the body may give rise to cancerous degenerations, and sometimes even to several different types. Each of the disorders in turn has its own features. The causes leading to these diseases are often very heterogeneous.
Despite this diversity, virtually all tumors and cancerous degeneration arise through very similar fundamental molecular or cellular processes. Research in the last two decades has made astonishing advances in knowledge concerning the most fundamental processes of carcinogenesis and tumorigenesis at the molecular level.
The genetic information is carried by the DNA molecules of the chromosomes in the cell nucleus. Two classes of genes which together account for only a small fraction of the total endowment of a cell play an essential role in the development of cancer, namely in particular proto-oncogenes (cancer gene precursors) and tumor suppressor genes (genes which suppress tumors). In their normal form, they direct the life cycle of the cell, they control the complicated sequence of processes by which a cell becomes larger and, if required, divides. Whereas proto-oncogenes promote cell growth, it is retarded by tumor suppressor genes. Together, these two classes of genes are responsible for a large part of the uncontrolled cellular proliferation processes in human tumors: if, for example, a proto-oncogene mutates in the regulatory region or in the structural region, it is possible that there is then production of too much of its growth-promoting protein, or that the latter is then excessively active; the proto-oncogene has become a cancer-favoring oncogene which stimulates the cells to excessive proliferation. By contrast, tumor suppressor genes contribute to the development of cancer if they are inactivated by mutations; as a consequence, the cell loses suppressor proteins capable of functioning, and thus crucial growth retarders which normally prevent it from inappropriate proliferation.
An emergency mechanism against unlimited proliferation is incorporated into normal body cells, and comprises a type of counter which records every cell division and calls a halt after a certain number of generations. After a certain number, which can be approximately predicted, of cell divisions or doublings, growth of normal cells ceases. This process is referred to as cell aging or senescence.
Responsible at the molecular level for this process of cell aging or senescence are the DNA fragments at the ends of the chromosomes, called the telomeres. They record as it were how many proliferation cycles a cell population experiences and, after a particular time, initiate senescence or the crisis. In this way they limit the ability of a cell population to grow unrestrictedly. In most healthy human cells, the telomeres are shortened by a small piece when the chromosomes are replicated at each cell division. When they have shrunk to a particular critical length, this is the signal for the cell to enter the stage of senescence; if the cell ignores the warning, the telomeres are shortened further until finally the crisis occurs: when telomeres are extremely short, chromosomes are linked together or fragment, and the induced genetic chaos is lethal for the cell.
The aging or senescence process in normal cells, i.e. the loss of the ability to divide, to which normal cells are subject, is thus dependent on chromosomes in normal mortal cells losing about 50 to 200 DNA nucleotides at their telomeric ends at each cell division. Loss of these terminal nucleotides (telomeres) has the function of a type of mitotic clock which records the number of cell divisions. Retention of telomeres appears to be necessary for cells to escape the senescence process and be able to divide indefinitely.
The protective mechanism described above is inactivated during the course of degeneration in most cancer and tumor cells, specifically by activation of a gene which contains the instructions for synthesizing an enzyme called telomerase. This enzyme systematically replenishes the telomere sections which are otherwise shortened, and thus permanently maintains them and makes the cell able to divide further virtually without limit. Thus, in most neoplastic and cancerous diseases, the immortality of the cells results from the retention of short but stable telomeres owing to the action of telomerase. The resulting potential immortality of the cells is unfavorable in several ways: firstly, it contributes to the possibility of a tumor becoming very large, and secondly it gives precancerous or already genuine cancer cells time to accumulate further mutations which increase their abilities to proliferate, to penetrate into other tissues and finally to metastasize.
It has been found that the unlimited cell growth of degenerate cells is based in about 80% of all neoplastic diseases on impaired regulation of telomerase. The treatment of neoplastic or cancerous diseases via telomerase inhibitors therefore appears to make a promising therapy possible for these diseases. Consequently, many attempts have already been made in the art to develop active ingredients for inhibiting telomerase.
Thus, for example, WO 00/74667 A2 proposes the use of telomerase inhibitors (e.g. AZT) in combination with an active ingredient which induces telomere destruction (e.g. paclitaxel) for cancer treatment. WO 99/65875 A1 and U.S. Pat. No. 5,863,936 propose the use of specific heterobicyclic systems as telomerase inhibitors for the therapy of cancerous diseases. Catechol derivatives like those described in European published specification EP 0 938 897 A1 are said likewise to be employable as telomerase inhibitors for cancer treatment.
Attempts are also made in the art to intervene by other mechanisms at the molecular or cellular level in the proliferation of tumor or cancer cells. Thus, neoplastic or cancerous diseases are treated in the state of the art by employing many alkylating agents which, via alkylation of the DNA, eventually induce direct damage of the DNA of the tumor or cancer cells (e.g. cyclophosphamide, ifosfamide, carmustine, chlorambucil, etc.). Likewise used for tumor or cancer therapy are substances which, via inhibition of topoisomerases, intervene in the replication of the tumor or cancer cells (e.g. camptoceticin, 9-aminocamptothecin, irinotecan, topotecan, doxorubicin, etc.) (cf., for example, Clive Page et al., Integrated Pharmacology, Mosby, 1997).
Whereas—besides alkylating active ingredients—there are some topoisomerase inhibitors in clinical use, at present no active ingredient is in clinical use for the treatment of various tumors which acts via inhibition of telomerase or combines the properties of inhibition of topoisomerase and of telomerase.